PROJECT SUMMARY Antiretroviral therapy (ART) has proven remarkably successful in decreasing the viral load in HIV-infected individuals but there are potential off-target effects that can result in the emergence of neurocognitive impairments and/or psychiatric symptoms. To better predict which individuals may be susceptible to side effects, we need a better mechanistic understanding of how ART drugs may be affecting the human central nervous system. Although animal models and postmortem analyses provide critical information, additional complementary approaches are needed to bridge the gap between these models and identify biomarkers and cellular signatures of ART. Recently, the introduction of methodology to generate human induced pluripotent stem cells (iSPCs) allows for the generation of a renewable resource of any cell type in human body. For neurological and psychiatric disorders in particular, this approach holds the promise of facilitating controlled investigations using human neurons to understand how genetic and environmental perturbations may alter cellular function and trigger widespread pathology in neural circuits. This project is designed to evaluate the molecular, cellular, and functional impact of several ART drugs on different subtypes of human neurons. We will use a combination of approaches to generate a comprehensive profile of the effects of these drugs at the single cell level in both cortical glutamatergic neurons and GABAergic neurons. Successful completion of these experiments will generate single cell transcriptomic and epigenomic datasets for the research community and could lead to the identification of cell-type specific novel pathways and targets of ART drugs. This platform will also provide a foundation to investigate individual variability in response to ART drugs and a potential diagnostic tool to guide treatment decisions.